Congenital Hypopituitarism

Jennifer MillerPediatric Endocrinology

Outline• Anatomy of the Hypothalamus and

Pituitary• Anterior Pituitary Development• Congenital Hypopituitarism

• Etiology• Presentation• Diagnosis• Treatment

Hypothalamus

Controls the release of 8 major hormones by the hypophysis and is involved in:1. Temperature regulation2. Control of food and water intake3. Sexual behavior and reproduction4. Control of daily cycles in the

physiological state and behavior5. Mediation of emotional responses

“Biological Clock”Projection from retina to suprachiasmatic nucleus

Day-night informationSynchronizes diurnal or circadian rhythms

HypothalamusConsists of large number of nuclei and fiber tractsSupraoptic and paraventricular nuclei – AVP, Oxytocin

• AVP and Oxytocin are transported down the nerve axons through infundibulum to the neurohypophysis

Arcuate Nucleus and others -releasing or inhibiting factors

• Secreted from terminals of these neurons enter portal system of vessels and carried to the adenohypophysis

• Anti-diuretic hormone (ADH): increases water absorption into the blood by the kidneys• Corticotropin-releasing hormone (CRH): CRH stimulates release of ACTH from anterior

pituitary -> adrenal glands to release corticosteroids -> regulate metabolism and immune response

• Gonadotropin-releasing hormone (GnRH): GnRH stimulates the anterior pituitary to release follicle stimulating hormone (FSH) and luteinizing hormone (LH) -> normal functioning of the ovaries and testes.

• Growth hormone-releasing hormone (GHRH) or growth hormone-inhibiting hormone (GHIH) (also known as somatostain): GHRH -> anterior pituitary release of growth hormone (GH); GHIH has the opposite effect. GH maintains healthy body composition (muscle/fat mass) and growth

• Oxytocin: role in orgasm, the ability to trust, body temperature, sleep cycles, and the release of breast milk.

• Prolactin-releasing hormone (PRH) or prolactin-inhibiting hormone (PIH) (also known as dopamine): PRH -> anterior pituitary to stimulate breast milk production via prolactin. PIH inhibits prolactin, and thereby, milk production

• Thyrotropin releasing hormone (TRH): TRH -> thyroid stimulating hormone (TSH) -> stimulates release of thyroid hormones -> regulate metabolism, energy, and growth and development

Hormones secreted by the hypothalamus

Pituitary

Size of a pea – approx 0.5 gramsLocated - sella turcica at base of

hypothalamusComposed of 2 functionally

distinct structuresAdenohypophysis (anterior pituitary)

Neurohypophysis (posterior pituitary)Differ in embryologic

development and anatomy

Anatomy of Pituitary

Central signaling integrator ofGROWTHREPRODUCTIONHOMEOSTASIS

Two components:• Adenohypophysis

receives signals through portal system of blood vessels from hypothalamus and through stalk) and

• neurohypophysis (receives signal through axons that arise in neural bodies in hypothalamus and also traverse down stalk)

Physiology of Pituitary Development

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AnteriorUp-growth of ectodermal cells from Rathke’s pouch

PosteriorDown-growth of neural tissue cells from the hypothalamus

Physiology of Pituitary Development

Dual embryonic origin: Anterior &

Intermediate Lobes

Infundibulum & Posterior Lobe

ORAL ECTODERM &

NEUROECTODERM

Two key concepts are TEMPORAL and SPATIAL relationships

Anterior Lobe of PituitarySignaling molecules

&Transcription

factors

5Different

Cell Types

6 Hormones

HESX1PROP1POU1F1LHx3LHx4TBx19SOX3SOX2

SomatotropesThyrotropesCorticotropesGonadotropesLactotropes

GHTSHACTHLHFSHPrl

SomatotropesThyrotropesCorticotropesGonadotropesLactotropes

Five cell types of anterior pituitary

Corticotrophs POMC -> ACTH

Somatotrophs GH

Lactotrophs PRL

Gonadotrophs LH/FSH

Thyrotrophs TSH

% pituitary cell population

40-50%

15-20%

10-20%

10-15%

3-5%

3 stages of anterior pituitary development

1. Induction of pituitary placode – thickened plate of ectoderm

2. Formation of Rathke’s pouch - the primordium of the anterior pituitary which undergoes cell proliferation and determination

3. Terminal differentiation of 6 hormone secreting lineages

Regulation of the development of the anterior pituitary gland by transcription factors. Following, inductive signals between the developing diencephalon and the oral ectoderm, early transcription factors guide the formation of rudimentary Rathke's Pouch (rRP) and then subsequent gene regulatory pathways control the determination, proliferation, and differentiation events that establish the specialized hormone-secreting cells.

Induction of pituitary placode

Physiology of anterior pituitary development

Evagination of oral ectoderm –induced by ventral diencephalonBMP4 – required for organ commitment of ant pit glandFGF8 – opposes BMP2 and is essential for cell survival

Rudimentary Rathke’s pouch produces signaling proteinsBMP2 – provides ventralizing cueWNT4 – cellular proliferation

Antagonistic relationship between signals

Early transcription factors

Expansion of Rathke’s pouch begins with cellular proliferation induced by early transcription factors:PITX1, PITX2, LHX3, LHX4, HESX1, SIX6

HESX1 – paired-like class of homeodomain transcription factor

REPRESSOR and acts by recruiting co-repressorsMechanism for temporal organization – eg. HSX1 and PROP1

HSX1 heterodimerizes with PROP1 - inhibits gene activation properties

Disorder of HSX1Recessive or dominant inheritanceImportant for development of optic nerveClinical manifestation:

Anterior pituitary hypoplasia/ectopic post pituitary/absent infundibulum

Absent corpus callosumWhat d/o does this sound like?

SOD

LHX3 - LIM homeodomain transcription factor

LHX3 is essential for proliferation and differentiation of almost all pituitary cells except corticotropes

Disorder of Lhx3Recessive inheritanceLhx3 mutations cause

deficiency in GH, PRL, TSH, LH, FSHRigid cervical spineHypo or hyperplastic anterior pituitary

Disorders of PROP1Recessive inheritancePROP1 mutations cause failure of initial proliferation

PIT1 dependent cell types

GonadotropinsLimited elbow extensibility, blue sclera, large sella turcica

MRI can show hyperplastic anterior pituitary –pseudotumor

(absence of PROP1 results in unopposed persistence of HESX1 expression which is involved in initial exponential proliferation)

Terminal lineage differentiationMore specific transcription factors are responsible for terminal cell type differentiation

PIT1, GATA2, TPIT

POUF1domain protein1. Directly controls regulatory genes

- Required for terminal differentiation of:- Somatotrope- Lactotrope- Thyrotrope

2. Protects from programmed cell death- Inactivation of POUF1 from a dominant negative mutation leads to

decreased growth rate and cell death- Hypoplasia of the gland

POUF1 domain proteinModel - transition from positional identity to cell-autonomous commitment

Spatial interaction - targeted expression of PIT1 ventrally can convert gonadotropes to thyrotropes - dorsal expression of GATA2 can convert all PIT1-dependent cells to gonadotropes

Terminal lineage differentiation

Tbx19 – T box transcription factorSpecific to corticotrope lineageActivate POMC promoter

Lack of one or more pituitary hormones leading to a loss of function in the gland or organ controlled by that hormone

Hypopituitarism

• Growth Hormone – stimulates growth of tissues and bone; lipolysis

• ACTH – Stimulates the adrenal gland to release cortisol to maintain blood pressure and blood sugar

• LH/FSH – controls sexual function and fertility• TSH – Stimulates thyroid gland to release thyroid

hormone• Prolactin – stimulates female breast development

and milk production

Anterior Pituitary Hormones

Growth Hormone• Secretion

• GH-releasing factor• Inhibition

• Somatostatin• Stimulates most body cells to

increase in size and divide• Major targets are bone and skeletal

muscle• Promotes protein synthesis• Encourages use of fats for fuel thus

conserving glucose• Most effects are mediated either

directly or indirectly by IGFs

• In children -> slowing or lack of growth and an increase in body fat

• Infants with GH deficiency are NOT born SGA. They are normal weight and length at birth.

• In childhood hypopituitarism, GH is the most commonly affected• Incidence rate of 1:3500 in US

47% due to tumors (craniopharyngioma)

15% CNS malformation

14% SOD

Radiation, leukemia, trauma, histiocytosis and CNS infection

GH deficiency

● Hypothalamus senses low T3 & T4 and releases TRH

● Anterior pituitary releases TSH & prolactin

● Thyroid makes T3 & T4

Hypothalamic Pituitary Thyroid Axis

TSH

Secretion• TRH

Inhibition• Thyroid Hormone

Actions• Increases iodide uptake,

thyroglobulin and thyroid hormone synthesis

Deficiency is a cause of congenital hypothyroidism

ACTHSecretion

CRF from hypothalamusPro-opiomelanocortin (POMC)

ACTHendorphinsMelanocyte stimulating hormones

InhibitionCortisol from adrenalsProlonged steroid use

Infants do not establish a diurnal pattern of cortisol release until 6 months of age.

● Hypothalamus senses low cortisol or threat to homeostasis

● Releases CRH● Ant pituitary releases ACTH● Adrenal gland makes cortisol● Cortisol → negative feedback

loop on pituitary and hypothalamus

● ADH also causes release of ACTH

Hypothalamic Pituitary Adrenal Axis

Symptoms include weakness, fatigue, weight loss, abdominal pain, hypotension, hypoglycemia and hyponatremia (with normokalemia) –unlike CAH because mineralocorticoid function regulated by the RAS

Hyponatremia in adrenal insufficiency is due to inappropriate increase in vasopressin secretion/action (cortisol Nly exerts tonic inhibitory effect on vasopressin secretion) and inability to excrete free water

• Severe stress - infection or surgery –precipitate adrenal crisis, coma and death

ACTH deficiency

Isolated ACTH Deficiency

Adrenal insufficiency: hypoglycemia, cholestasis, and hyponatremiaHypopigmentation with red hairEarly onset morbid obesity

Gonadotropins- Secretion

GnRHHypothalamus sends pulses

Increases during puberty

- InhibitionInhibin

FSHSpermatogenesis Follicular maturation

LHTestosteroneEstradiol

Hypothalamic Pituitary Gonadal Axis

● Hypothalamus senses low sex hormones

● Releases GnRH● Ant pituitary releases LH & FSH

→ estrogen & testosterone production

● Gonads produce inhibin → neg feedback

● Pituitary produces follistatin, which inhibits activin → neg feedback

Prolactin• Most important regulator is dopamine which acts on D2

receptors of lactotrophs causing INHIBITION of prolactin secretion

• TRH has a stimulatory effect on prolactin release

• Prolactin suppresses GnRH secretionHyperprolactinemia

GalactorrheaPituitary adenomas

Medications that can cause hyperprolactinemiaNeuroleptics, antipsychotics, estrogens and anti-hypertensives

● Paraventricular nucleus and supraoptic nucleus produces:

○ Oxytocin - uterine contraction, lactation

○ Vasopressin -water reabsorption from distal and collecting tubule of kidney; concentrate urine.

Hormones of Posterior Pituitary

Posterior PituitaryVasopressin (AVP or ADH)

Released in response to increased osmotic pressure in the bloodWater balance

Increased reabsorption of water in collecting ducts of kidneysArteriolar vasoconstriction – HTNIncreased thirst

OverproductionHead trauma, brain tumors, encephalitis, pneumoniaSIADH

HA, apathy, nausea, vomiting, impaired consciousnessDecreased plasma osmolarity

UnderproductionCentral Diabetes Insipidus (DI)

Pituitary tumors, head trauma, infiltrative diseases, autoimmune or surgical

Increased plasma osmolarity

Posterior PituitaryOxytocin

Stimulates the smooth muscle of the uterus to contract, inducing labor.

Stimulates the myoepithelial cells of the breasts to contract which releases milk from breasts when nursing.

Stimulates maternal behavior.In males it stimulates muscle contractions in the prostate gland to release semen during sexual activity

Clinical Presentation of Congenital Hypopituitarism

• Manifestations that suggest congenital anterior hypopituitarism include midline defects, micropenis, optic atrophy, hypoglycemia, and poor growth.

• Can occur from birth trauma, asphyxia, part of a number of midline defects, or due to a genetic mutation involving the anatomic development of the pituitary gland.

Congenital Hypopituitarism

• Most common midline defect is septo-optic dysplasia. • This disorder includes absence of the septum pellucidum in 50% of cases

and underdevelopment of the optic nerves, associated with variable degrees of reduced vision ranging from mild loss to complete blindness.

• Affected children may present with nystagmus. • For any child noted to have optic nerve hypoplasia, at least a one-time

referral to a pediatric endocrinologist is warranted, especially if there is any associated growth delay.

• Other midline associations with hypopituitarism include the presence of a fused deciduous upper central maxillary incisor cleft lip and/or palate, choanal atresia, anomalous and/or absent vascular supply to the central nervous system, and encephaloceles

Congenital Hypopituitarism: Midline Defects

• One of the earliest known transcription factor genes involved in embryogenesis of the pituitary gland is Rathke's pouch homeobox, (called HESX1), mutations of which have been found in a few cases of septo-optic dysplasia.

• Other early transcription factor genes important in the formation of various pituitary cell populations are LHX3, LHX4, and PROP-1 (Prophet of Pit-1), and PIT-1/POUF1. Mutations of LHX3 are associated with deficiencies of all anterior pituitary hormones ACTH along with a rigid cervical spine leading to limited head rotation,

• PROP-1 mutations are associated with deficiencies of GH, prolactin, TSH, and sometimes gonadotropins and ACTH, limited elbow extensibility, blue sclerae, and, a large sella turcica in some

• PIT-1/POUF1 is a pituitary-specific transcription factor that is necessary for the development of somatotroph, lactotroph, and thyrotroph lineages, so mutations of PIT-1 are associated with deficiencies of GH, prolactin, and TSH.

Congenital Hypopituitarism: Genetic Defects

Congenital Hypopituitarism

Septo-Optic Dysplasia/Optic Nerve Hypoplasia

Triad of:Hypoplastic optic disk with characteristic double marginAbsent septum pellucidum and corpus callosumPituitary hormone abnormality – most commonly GHD

Highly variable phenotype

60% have isolated hypopituitarism

30% have all 3 manifestations

Optic disk double marginDue to underdevelopment of the

optic nervesVariable degrees of reduced vision

ranging from mild loss to complete blindness.

Affected children may present with nystagmus

Any child noted to have optic nerve hypoplasia, a one-time referral to a pediatric endocrinologist is warranted, especially if there is any associated growth delay

Neonates with nystagmus must have pituitary function evaluated

SOD

• Most common symptom is hypoglycemia due to GH deficiency with or without ACTH deficiency

• Cortisol and GH are counter-regulatory hormones that protect against hypoglycemia

• Without one or both, insulin acts in an unopposed fashion• In any term infant who develops hypoglycemia with no underlying

risk factor (such as prematurity, intrauterine growth retardation, infant of a diabetic mother, etc), the diagnosis of hypopituitarism must be considered.

Symptoms of Congenital Hypopituitarism

Severe cortisol deficiency may result in presentation with hyponatremia (as cortisol is necessary for the action of ADH to facilitate the excretion of free water by the kidneys) and/or outright shock due to its effects on blood pressure maintenance. If DI were present, shock with hypernatremia would manifest.

Symptoms of Congenital Hypopituitarism

• Some children with congenital hypopituitarism develop a unique, noninfectious form of hepatitis. The condition is suspected if there is liver enlargement and abnormal liver function tests (predominantly indicating cholestasis) and is confirmed by the presence of characteristic giant-cell transformation of hepatocytes as seen on biopsy.

• The exact cause of this giant-cell hepatitis is unknown, and the condition usually remits on its own over the first few months of life without any permanent damage to the liver.

Considerations for Congenital Hypopituitarism

Diagnosis of hypopituitarism• Clinical indications for evaluation of congenital

hypopituitarismü #1 Hypoglycemia (GHD/ACTH def)ü Micro phallus (GHD/Gndtr def)ü Jaundice (GHD/thyroid deficiency)ü Growth failure

• Hormone testing Gonadotropin window of opportunityNewborn screen suffice for thyroid ?Serum cortisol - @ 8am ?GH stimulation – insulin, glucagon, arginine, clonidine

• Imaging: MRI

Hormone deficiency is treated by replacing the deficient hormones. The goals of treatment are to improve symptoms and to replace the deficient hormone or hormones at a level that is as close to physiologically correct as possible.

However, one rule of hormone replacement is that no one dose will suit every patient. Thus, the patient will need to be seen regularly after starting treatment to assess the effect. It often takes time and repeated dose changes to find the optimal dose for each patient.

Treatment

TreatmentHormone replacement therapy

1. GHD: GH replacement therapy2. Central hypothyroidism: Levothyroxine usually ½ the

dose needed to treat primary hypothyroidism; follow levels of fT4

3. Gonadotropin deficiency: replace sex steroids vs gonadotropins (estrogen and progesterone or testosterone) needed at puberty [not address fertility]

4. Central adrenal insufficiency: replacement of cortisol; lower dose compared to treatment of CAH 10-15 mg/m2/day; stress hormone therapy

**If patients have multiple pituitary hormone deficiencies, cortisol should always be the first hormone replaced as medications like thyroid hormone or GH can increase the body’s need for cortisol.

TreatmentTreatment considerations

Adrenal replacement before thyroidAdrenal replacement may unmask DI (treated with oral desmopressin 0.1-0.2 mg tablets)

Mineralocorticoid function ?SOD

Optical problems - generally not treatableVision, physical, and occupational therapies may be required

You have a 1 week old boy in your office for evaluation. Parents tell you that the infant is jittery, irritable, and jaundiced. You note that the penis looks a bit small. Of the following, which is the most likely physical abnormality you will find on examination?

A. Bilateral ear tagsB. Cleft palateC. Club feetD. Polydactyly

Board Question

You are evaluating a patient in clinic and notice the abnormality pictured. Which of the following is most likely to be affected?

A. Growth hormone levelsB. Aldosterone levelsC. Catecholamine levelsD. Insulin levels

You are on call in the PICU and following a very sick patient admitted with meningococcal meningitis. He has not had any urine output in the last 8 hours despite fluid administration. You order a BMP and his Na is 125. What is the most likely cause of the hyponatremia in this patient?

A. Diabetes insipidusB. Psychogenic polydipsiaC. Inappropriate fluid administrationD. SIADH

Questions?